1. Field of the Invention
The present invention relates to novel 2-ureido-benzamide derivatives having potent acyl coenzyme A:cholesterol acyltransferase (ACAT: EC2.3.1.26) inhibiting activity, to pharmaceutical composition containing these compounds and to use thereof for the treatment and prevention of atherosclerosis.
Ischemic circulatory diseases such as myocardial infarction and cerebral infarction resulting from atherosclerosis have been a major cause of human death. The studies on atherosclerosis have been carried out in the various fields for long years.
Recently, it has been found that esterification of intracellular cholesterol is effectively catalyzed by the enzyme: ACAT which is found later in various tissues such as liver, intestine, adrenal and macrophages. It is said that ACAT may be present in all tissues The Enzymes, 16, 523-539 (1983)!.
In intestine, ACAT plays a key role in the gastrointestinal absorption of cholesterol. In intestinal mucosal cells, dietary and biliary cholesterol derived from the diet and biosynthesis must be esterified by the action of ACAT before it can be incorporated into the chyromicron particles which are then released into the blood stream Eur. J. Clin. Invest., 9, 55 (1971)!. Thus inhibition of ACAT in intestinal mucosa appears to block intestinal absorption of cholesterol, resulting in the decrease of blood cholesterol level. However, such an intestinal ACAT inhibitor may involve unfavorable increase of the endogenous cholesterol synthesis and possible ineffectiveness of such inhibitor on patients having no hyper-function in cholesterol absorption.
Although the role of ACAT in liver, especially in human, is less clearly known, the ACAT may participate in the synthesis and secretion of VLDL and the control of biliary excretion of cholesterol J. Lipid Res., 26, 647 (1985)! and inhibition of the liver ACAT may result in lowering of the blood lipid level.
Cholesterol esters are a major component of atherosclerotic lesions and also a major storage form of cholesterol in arterial wall cells. Accumulation of cholesterol esters is linked to the form cell formation which is catalyzed by ACAT in macrophages. Thus, inhibition of the macrophage ACAT may prevent directly the progression of atherosclerotic lesion formation by decreasing the form cell formation without unfavorable effects as in the case of ACAT inhibition in intestine.
2. Description of the Prior Art
Certain phenylurea derivatives having ACAT inhibiting activity are disclosed as shown below.
(a) U.S. Pat. No. 4,623,662 (1986) discloses substituted urea and thiourea compounds such as ##STR5##
(b) EP Publication No. 477,778 (1992) and J. Med. Chem., 36, No. 11, 1641-1653 (1993) disclose benzene, pyridine and pyrimidine derivatives such as ##STR6##
(c) EP Publication No. 370,740 (1990) discloses diaryl compounds as inhibitors of ACAT such as ##STR7##
(d) U.S. Pat. No. 5,116,848 (1992) discloses N-phenylalkyl(thio)urea derivatives such as ##STR8##
(e) A variety of urea compounds can be found in the other literatures, for example, in EP Publication Nos. 335,375 (1989), 405,233 (1991) and 447,116 (1991) and in U.S. Pat. Nos. 4,923,896 (1990), 5,015,644 (1991) and 5,106,873 (1992).
On the other hand, phenylurea derivatives having other pharmacological or agricultural activities such as blood sugar lowing activity, 5-HT M-receptor antagonist activity and herbicidal activity are disclosed in JP Unexamined Publication No. 59-181,257 (1984) Chem. Abst., 102, No. 78735 (1985)!, EP Publication No. 235,878 (1987) and U.S. Pat. No. 3,812,168 (1974), respectively. And some organic reactions for phenylurea derivatives are disclosed in literatures such as Indian J. Chem., 266 No. 12, 1133-1139 (1987) and Mh. Chem., 98, No. 3, 633-642 (1967).
However, there are no known literature references disclosing such 2-ureido-benzamide derivatives as those in this invention and their use as ACAT inhibitors for the treatment of atherosclerosis.
The present inventors synthesized various novel 2-ureido-benzamide compounds having substituents on both of amide and urea(ureido) nitrogen atoms and intensively investigated their activities, and, as the result, found that the useful as a drug for atherosclerosis and related diseases.